Development of Pathology-activated Drugs for Treatment of Neuropathic Pain

目前用于神经性疼痛的疗法效果不佳。一个可能的原因是，目前的治疗方法只针对单一的生化机制或途径，而慢性疼痛是一个多机制的问题。富马酸盐，如富马酸单甲酯（MMF），由于其组合的抗氧化剂和抗炎特性，独特地定位于治疗疼痛的多机制问题。然而，由于其不良的胃肠道耐受性和不加选择的免疫干扰，阿托伐他汀治疗慢性疼痛的风险-获益比是不可接受的。该研究项目建议通过设计新的MMF前药，通过设计非反应性前药来改善耐受性，从而建立在已记录的阿托伐他汀类药物的镇痛疗效基础上。为了减少全身免疫干扰，前药将进一步设计为仅在疼痛神经轴中ROS/RNS过度产生的情况下优先释放活性代谢物MMF。总体目标是开发一种1，2-二羰基前药，其优先在病理部位释放MMF以减轻神经性疼痛，同时减少由谷氨酸盐的全身分布引起的不良反应。初步数据表明，抗氧化主调节核因子红细胞2相关因子2（NRF2）是一个主要的治疗目标。使用经验证的NRF 2激活剂和标准治疗剂作为对照药物，UG3的具体目标是：1）完成1，2-二羰基MMF前药先导药物的初步表征; 2）优化先导化合物，设计和评价备用1，2-二羰基MMF前药; 3）表征安全性，验证1，2-二羰基MMF前药先导药物和备用前药的镇痛疗效。探索性里程碑将确定一个先导分子和备用分子。这些化合物将在以下UH3阶段特定目标下通过IND使能研究推进：4）候选物的广泛PK/PD表征; 5）在已建立的神经性疼痛啮齿动物模型中证明体内功效; 6）剂量范围探索以建立最大耐受剂量（MTD）以及心血管、呼吸和胃肠道安全性和毒性研究;以及7）建立一个牵头开发团队，以完成IND申请。BPN资源将用于CMC生产和规模扩大，以及1期临床试验计划的开发。该项目的成功完成将通过将非阿片类药物治疗剂（MMF）靶向激活递送至疼痛病理局部区域产生重大影响。MMF的位点特异性释放将减少其不良反应，消除基于MMF的神经性疼痛治疗的最后障碍。

Current therapeutics for neuropathic pain are poorly efficacious. One likely reason is that current therapies target only a single biochemical mechanism or pathway while chronic pain is a multi-mechanism problem. Fumarates, such as monomethyl fumarate (MMF), are uniquely positioned to treat the multi-mechanism problem of pain due to their combined antioxidant and anti-inflammatory profile. However, the risk-benefit ratio of fumarates is unacceptable for treatment of chronic pain, given their poor gastrointestinal tolerability and indiscriminate immune interference. This research project proposes to build on the documented analgesic efficacy of fumarates by designing new MMF prodrugs that have improved tolerability through design of non-reactive prodrugs. To reduce systemic immune interference, prodrugs will further be designed to preferentially release MMF, the active metabolite, only where ROS/RNS are overproduced in the pain neuraxis. The overall objective is to develop a 1,2-dicarbonyl prodrug that preferentially releases MMF at sites of pathology to alleviate neuropathic pain, while reducing adverse effects caused by systemic distribution of fumarates. Preliminary data indicate that the antioxidant master regulator nuclear factor erythroid 2-related factor 2 (NRF2) is a major therapeutic target. Using validated NRF2 activators and standard of care therapeutics as comparators, the UG3 specific aims are: 1) Complete initial characterization of the lead 1,2-dicarbonyl MMF prodrug; 2) Optimize lead compound, and design and evaluate backup 1,2-dicarbonyl MMF prodrugs; and 3) Characterize safety, validate analgesic efficacy of lead and backup 1,2-dicarbonyl MMF prodrugs. The exploratory milestones will identify a lead and backup molecules. These compounds will be advanced through IND-enabling studies under the following UH3 phase specific aims: 4) Extensive PK/PD characterization of candidates; 5) demonstrate in vivo efficacy in established rodent models of neuropathic pain; 6) Dose range finding to establish maximal tolerated dose (MTD) and cardiovascular, respiratory and gastrointestinal safety and toxicity studies; and 7) establish a Lead Development Team to finalize an IND application. BPN resources will be engaged for CMC manufacture and scale up, and development of a phase 1 clinical trial plan. Successful completion of this project will have major impact by first-in-class target activated delivery of a non-opioid therapeutic agent (MMF) to localized regions of pain pathology. Site-specific release of MMF will reduce its adverse effects, eliminating the final hurdles to MMF- based treatment of neuropathic pain.